This invention relates to benzob!1,4!diazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin in mammals.
Cholecystokinin (CCK) is a peptide found in the gastrointestinal tract and the central nervous system. see A. J. Prange et al., Ann. Reports Med. Chem. 17, 31, 33 (1982), J. A. Williams, i Biomed Res. 3, 107 (1982) and V. Mutt, Gastrointestinal Hormones, G. B. J. Green, Ed., Raven Press, N.Y. CCK has been implicated inter alia as a physiological satiety hormone involved in appetite regulation, see Della-Ferra et al, Science, 206, 471 (1979), Saito et al., Nature, 289, 599, (1981), G. P. Smith, Eating and its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 67 (1984), as a regulator of gallbladder contraction and pancreatic enzyme secretion, an inhibitor of gastric emptying, and as a neurotransmitter, see A. J. Prange, supra, J. A. Williams, Biomed Res., 3, 107 (1982), J. E. Morley, Life Sci. 30, 479, (1982). Gastrin is a peptide involved in gastric acid and pepsin secretion in the stomach, see L. Sandvik, et al., American J. Physiology, 260, G925 (1991), C. W. Lin, et al., American J. Physiology, 262, G1113, (1992). CCK and gastrin share structural homology in their C-terminal tetrapeptide: Trp-Met-Asp-Phe.
Two subtypes of CCK receptors have been identified, designated as CCK-A and CCK-B, and both have been found in the periphery and central nervous systems. It has recently been reported that CCK-B receptors are similar to the gastrin receptor, see Pisegna, J. R., de Weerth, A., Huppi, K., Wank, S. A., Biochem. Biophys. Res. Commun. 189, 296-303 (1992). CCK-A receptors are located predominantly in peripheral tissues including the pancreas, gallbladder, ileum, pyloric sphincter and vagal afferent nerve fibers; CCK-A receptors are found to a lesser extent in the brain, see T. H Moran, et al., Brain Res., 362, 175-179 (1986), D. R. Hill, et al., Brain Res, 4545, 101, (1988), D. R. Hill, et al., Neurosci Lett., 89, 133, (1988), R. W. Barret, et al., Mol. Pharmacol., 36, 285, (1989), D. R. Hill, et al., J. Neurosci, 10, 1070 (1990), V. Dauge et al., Pharmacol Biochem Behac., 33, 637, (1989), while CCK-B receptors are found predominantly in the brain, see V. J. Lotti and R. S. L Chang, Proc. Natl. Acad. Sci. U.S.A., 83, 4923 (1986), J. N. Crawley, Trends Pharm. Sci., 88, 232, (1991).
The literature in the CCK area contains extensive discussion surrounding CCK antagonist activity relating to the increase of food intake and treating oncologic disorders, in particular through the use of 1,4- and 1,5-benzodiazepines, see B. E. Evans, Drugs of the Future, 14, 971 (1989), M. A. Silverman, et al., Am. J. Gastroenterol, 82, 703 (1987), EPO 0538 945, published Apr. 28, 1993, EPO 0 523 845, published Jan. 20, 1993, EPO 0284 256, published 28 Sep., 1988, and also relating to the regulation of anxiety, arousal, neuroleptic agents, and opioid-induced analgesia, see Lotti, supra, Crawley, supra, Singh, L., et al, Proc. Natl. Acad. Sci. U.S.A., 88, 1130 (1991).
On the other hand, CCK agonist activity has been linked to inhibition of food intake in animals and thus weight loss, see Della-Fera, et al, supra, K. E. Asin, et al, Intl. Conference on Obesity, abstract pp.40 (1990). It has been suggested that CCK acts in the periphery through vagal fibers and not directly on the brain to produce satiety, see Smith, G. P. and Cushin, B. J., Neuroscience Abstr., 4, 180 (1978), Smith, G. P., Jerome, C., Cushin, B. J., Eterno, R., and Simansky, K. J., Science, 212, 687-689, (1981). Compounds having CCK agonist activity have been reported to include peptide analogues, see U.S. Pat. No. 4,490,364, PCT WO 91/19733, published 26 Dec. 1991, K. Shiosaki et al., J. Med. Chem., 33, 2950 (1990).
The compounds of the present invention have been found to have CCK-A agonist activity, and therefore may be useful in part for inhibiting appetite, for inducing long-term weight loss in overweight patients and improving the cardiovascular and non-insulin dependent diabetes problems associated with these overweight conditions, and for treating obesity, gall bladder stasis and disorders of pancreatic secretion.
CCK has been shown to inhibit gastric emptying in humans and is thus useful for treatment of diabetes, particularly early noninsulin-dependent diabetes, through maintenance of the following glucose metabolic indicators at or near normal levels: blood glucose, C-peptide, insulin levels at fasting and during oral glucose tolerance tests, hemoglobin A1C, insulin resistance, GIP levels and CCK levels, see U.S. Pat. No. 5,187,154, which is incorporated herein by reference. The CCK-A agonist compounds of the present invention are therefore useful for treatment of diabetes in humans through stabilization of these glucose metabolic indicators.